This renewal application for the George M. O' Brien Kidney Research Center at the University of Washington focuses on the response of the kidney to several forms of injury with the goal of clarifying why renal diseases resolve or progress. The Center is composed of 5 scientific projects and 2 cores that bring together 3 basic scientists and 4 renal scientists from 4 separate departments. The studies proposed focus on 3 molecules of importance in the renal response to injury: cell cycle regulatory proteins, osteopontin and SPARC, with basic, applied and clinical studies proposed of each topic. In Project 1, Dr. Roberts will explore the role of several cell cycle proteins in regulatory cell growth, and in Project 2 Dr. Shankland will extend these observations to define the role of cyclin kinase inhibitors in causing hypertrophy of the glomerular epithelial cell in response to various stimuli in vitro and in vivo. In Project 3, Dr. Giachelli will continue studies of osteopontin is a mediator of interstitial inflammation/fibrosis focussing on interactions with TGFbeta, and in Project 4 Dr. Johnson will explore the mechanisms by which initial tubulointerstitial injury leads to salt-dependent hypertension. In Project 3, Dr. Sage will assess the mechanisms by which SPARC regulates TGFbeta and collagen production by glomerular mesangial and epithelial cells, and Dr. Couser will utilize SPARC knock-out and transgenic mice to define the role of SPARC in glomerular and interstitial renal disease in vivo. All five projects will pursue studies of cell cycle regulatory proteins, osteopontin and SPARC in human renal disease. It is anticipated that the studies proposed at basic, applied and clinical levels will advance the understanding of the renal response to injury and its consequences.